Traumatic brain injury (TBI) is the number one killer of adults under 45 years of age, with rehabilitative costs for survivors in the billions of dollars annually. Currently there are no treatments specific for long-term cognitive deficits and other neurological sequelae in survivors of TBI. Necrostatin-1 is a small molecule inhibitor of a novel form of programmed necrosis, termed necroptosis, which strikingly improves postinjury cell death as well as Morris water maze deficits even when administered after CCI. Pharmacokinetic data suggest a favorable brain penetration and half-life for necrostatin-1, while necrostatin-5 is almost twice as potent an inhibitor of necroptosis in vitro as necrostatin-1. Together, these data suggest that necrostatin-1, and possibly other necrostatins, may be clinically useful agents for the treatment of cognitive deficits after traumatic brain injury. The goal of this R21 application is to obtain preclinical proof of principle data that will justify carrying forward necrostatin-1 or necrostatin-5 (and potentially other necrostatins) into clinical trials for patients with severe TBI. To accomplish this goal we propose the following Specific Aims: (1) Determine the dose response of necrostatin-1 and necrostatin-5 administered intravenously before CCI on posttraumatic cognitive outcome;(2) Determine the therapeutic window of necrostatin-1 and necrostatin-5 administered intravenously after CCI on posttraumatic cognitive outcome;and (3) Determine the effects of necrostatins on histopathology (cellular permeability and axonal injury), and on motor and cognitive function at three injury severity levels of CCI. Outcome measures proposed are Morris water maze performance, vestibulomotor function (wire grip test), and histopathology. In all Aims, gender effects will also be assessed. Positive findings in this R21 application will be applied towards a UO1 application intended to bring necrostatins to clinical trials for patients with TBI. PUBLIC HEALTH RELEVANCE: Work in the proposed project could render a new treatment for patients with traumatic brain injury. This specific drug therapy might reduce brain cell death as well as improve learning and memory in long term survivors, and thereby improve their quality of life.